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Cited by 181Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyAlzheimer's disease research and treatments

Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders

Open access
MacDonald, K., Feifel, D.·2013·Frontiers in Neuroscience
DOI 10.3389/fnins.2013.00035PMC PMC3597931
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Abstract

Concerns regarding a drought in psychopharmacology have risen from many quarters. From one perspective, the wellspring of bedrock medications for anxiety disorders, depression, and schizophrenia was serendipitously discovered over 30 year ago, the swell of pharmaceutical investment in drug discovery has receded, and the pipeline's flow of medications with unique mechanisms of action (i.e., glutamatergic agents, CRF antagonists) has slowed to a trickle. Might oxytocin (OT)-based therapeutics be an oasis? Though a large basic science literature and a slowly increasing number of studies in human diseases support this hope, the bulk of extant OT studies in humans are single-dose studies on normals, and do not directly relate to improvements in human brain-based diseases. Instead, these studies have left us with a field pregnant with therapeutic possibilities, but barren of definitive treatments. In this clinically oriented review, we discuss the extant OT literature with an eye toward helping OT deliver on its promise as a therapeutic agent. To this end, we identify 10 key questions that we believe future OT research should address. From this overview, several conclusions are clear: (1) the OT system represents an extremely promising target for novel CNS drug development; (2) there is a pressing need for rigorous, randomized controlled clinical trials targeting actual patients; and (3) in order to inform the design and execution of these vital trials, we need further translational studies addressing the questions posed in this review. Looking forward, we extend a cautious hope that the next decade of OT research will birth OT-targeted treatments that can truly deliver on this system's therapeutic potential.

AI snapshot

Written from the paper’s full text.

TL;DR

This clinically oriented review argues that oxytocin (OT) is a promising target for CNS drug development, but that most human OT studies are single-dose studies in normals and do not yet establish efficacy in brain disorders. It identifies 10 key questions for future OT therapeutic research and calls for randomized controlled trials in actual patients alongside further translational studies.

Key findings

  • OT has been proposed as a potential treatment for addiction, anxiety disorders, autism-spectrum and other developmental disorders, borderline personality disorder, mood disorders, and schizophrenia; as of November 2012, ongoing intranasal OT trials were noted in autism, schizophrenia/schizoaffective disorder, frontotemporal dementia, major depressive disorder and treatment-resistant depression, PTSD, borderline personality disorder, and drug dependence.
  • Table 1 shows that most patient-targeted OT trials were single-dose; the smaller set of multiple-dose trials/case reports includes schizophrenia studies such as Feifel et al. (2010, 2012a) using 20 IU twice-daily for 1 week then 40 IU twice-daily for 2 weeks, which improved PANSS/CGI at 3 weeks and verbal memory; Pedersen et al. (2011) using 24 IU twice-daily for 2 weeks, which improved PANSS and social cognition; and Modabbernia et al. (2013) using 20 IU twice-daily for 1 week then 40 IU twice-daily for 8 weeks, which improved PANSS total, positive, and negative scales by week 4.
  • Dose-related findings are mixed: in schizophrenia, 10 IU decreased facial emotion recognition whereas 20 IU improved emotion recognition in polydipsic relative to non-polydipsic patients (Goldman et al., 2011); in fragile X syndrome, 24 IU but not 48 IU improved eye-gaze frequency, while 48 IU but not 24 IU decreased social-stress-induced salivary cortisol (Hall et al., 2012).
  • The review concludes that the OT system is an extremely promising CNS drug target, that rigorous randomized controlled trials targeting actual patients are pressing, and that further translational studies are needed to address the 10 questions posed.

Methods

  • Design: clinically oriented narrative review, not a systematic review or meta-analysis; it identifies 10 key questions (Table 2) relevant to developing OT-targeted therapeutics for brain disorders.
  • Data/sample: reviews extant preclinical, translational, and human OT literature, including Table 1 of studies using OT in patients with brain-based illness and a November 2012 note on ongoing treatment trials from clinicaltrials.gov.
  • Analysis: narrative synthesis of selected literature and clinical trial considerations; no primary data collection or quantitative pooling.

Limitations

  • Stated: the review has a necessarily limited scope, constrained to arenas of direct relevance to OT-based therapeutics; readers are referred elsewhere for OT neurophysiology, AVP interaction, OTR genetic variation, and human development.
  • Stated: the field lacks definitive patient-targeted trials—most published OT studies are single-dose studies in normals, patient-targeted clinical trials are relatively limited and mostly single-dose, few multi-week trials exist, and no published studies have examined the time course of brain-mediated effects of intranasal OT or their correlation with peripheral OT levels.
  • Evident: as a narrative review, it does not report systematic search or selection criteria, and Table 1 includes small samples, case reports, and mixed designs, limiting quantitative synthesis and generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fnins.2013.00035

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 221 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    No OT-related genetic syndrome akin to FNDI has yet been characterized in humans.

    “As such, although no OT-related genetic syndrome akin to FNDI has yet been characterized in humans, the abovementioned findings raise the interesting question of the possibility of an “OT-deficiency syndrome””
    Quote in the paperNot a substantial claim
  • Findingnone given

    The vast majority of published studies of IN OT-even those done in patient samples-have used only a single-application dosing paradigm.

    “The vast majority of published studies of IN OT—even those done in patient samples (Table 1)—have used only a single-application dosing paradigm.”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    Despite anticipation, few studies have actually delivered OT as a bona-fide therapeutic agent, using chronic daily dosing, targeting core symptoms of specific disease states, and assessing safety, tolerability, and clinical outcomes.

    “More precisely, despite an enormous amount of anticipation that OT's effects in preclinical studies can be translated into OT-based treatments for psychiatric disorders, few studies have actually delivered OT as a bona-fide therapeutic agent, using chronic daily dosing, targeting core symptoms of specific disease states, and assessing safety, tolerability, and clinical outcomes.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    As of November 2012, ongoing treatment trials of intranasal OT exist in autism, schizophrenia and schizoaffective disorder, frontotemporal dementia, major depressive disorder and treatment resistant depression, post-traumatic stress disorder, borderline personality disorder, and drug dependence.

    “As of November 2012, we note ongoing treatment trials of intranasal (IN) OT in autism, schizophrenia and schizoaffective disorder, frontotemporal dementia, major depressive disorder and treatment resistant depression, post-traumatic stress disorder, borderline personality disorder, and drug dependence (i.e., alcohol, marijuana) (www.clinicaltrials.gov).”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    The suggestion that OT may have therapeutic value in the treatment of a host of brain-based conditions has not for the most part been bolstered by clinical investigations with meaningful therapeutic endpoints.

    “Although it has been safely used for decades in obstetrics to induce and augment labor, the suggestion that OT may have therapeutic value in the treatment of a host of brain-based conditions (addiction, anxiety, autism, mood disorders, and schizophrenia) has not for the most part been bolstered by clinical investigations with meaningful therapeutic endpoints.”
    Quote in the paperSubstantial claim
  • May combine two claims. 46
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  • May combine two claims.

    Findingnone given

    To date, there have been a relatively limited number of patient-targeted clinical OT trials, with the majority being single-dose.

    “To date, however, there have been a relatively limited number of patient-targeted clinical OT trials, with the majority being single-dose (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Unpublished data from our group found that patients with depression had an anxiogenic response to single-dose IN OT given in a psychotherapy context, in contrast to acute anxiolytic effects reported in normals.

    “A second, unpublished set of data from our group found that patients with depression had an anxiogenic response to single-dose IN OT given in a psychotherapy context, in contrast to acute anxiolytic effects reported in normals (Heinrichs et al., 2003; de Oliveira et al., 2012a,b).”
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    • cites Heinrichs et al., 2003

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    • cites de Oliveira et al., 2012a

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    • cites de Oliveira et al., 2012b

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  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    The vast majority of published OT studies are single-dose studies in normals.

    “as mentioned, the vast majority of published OT studies are single-dose studies in normals”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The bulk of extant OT studies in humans are single-dose studies on normals and do not directly relate to improvements in human brain-based diseases.

    “the bulk of extant OT studies in humans are single-dose studies on normals, and do not directly relate to improvements in human brain-based diseases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Several potentially seminal clinical studies of oxytocin appear to be underway in several top target disorders.

    “In this regard it is noteworthy that—after a long period of gestation—the water seems to have broken on research directly testing OT's clinical promise: several potentially seminal clinical studies of OT appear be underway in several top “target” disorders (www.clinicaltrials.gov).”
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    • cites www.clinicaltrials.gov

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    Premisecitation

    Bartz et al. demonstrated that many patients with borderline personality disorder have divergent responses to OT than those seen in normals, with OT decreasing trust and cooperation.

    “Additionally, Bartz et al. has demonstrated that many patients with borderline personality disorder have divergent responses to OT that those seen in normals, with OT-decreasing trust and cooperation (Bartz et al., 2011a).”
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    • cites Bartz et al., 2011a

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    Premisecitation

    More than 60 clinically relevant genetic variants of the AVP prohormone have been identified.

    “Currently, more than 60 clinically relevant genetic variants of the AVP prohormone have been identified (Christensen et al., 2013).”
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    • cites Christensen et al., 2013

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    Premisecitation

    Acute and chronic effects of medications are often diametrically opposite, as seen with SSRIs, which are first-line chronic treatment for anxiety disorders yet can cause anxiety after a single dose.

    “Furthermore, as intimated above, the acute and chronic effects of medications are often diametrically opposite, as seen in the case of SSRIs, which are a first-line chronic treatment for anxiety disorders, yet can cause anxiety after a single-dose (Spigset, 1999; Birkett et al., 2011).”
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    Premisecitation

    Patients with FNDI present clinically with symptoms of progressive functional AVP deficiency, including polyuria and polydipsia.

    “Given endogenous AVPs role in natriuresis, these patients present clinically with symptoms of progressive functional AVP deficiency, including polyuria, and polydipsia (Robertson, 1995).”
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    • cites Robertson, 1995

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    Interpretationreasoning

    We should be circumspect when extrapolating too directly from single-dose studies in normals to the effects of chronic dosing in psychiatrically ill samples.

    “we should be circumspect when extrapolating too directly from these studies to the effects of chronic dosing in psychiatrically ill samples.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Testosterone promotes hypothalamic OTR-binding as well as production of AVP, which has many opponent actions to OT.

    “whereas testosterone promotes hypothalamic OTR-binding (Johnson et al., 1991) as well as production of AVP (Delville et al., 1996), which has many opponent actions to OT (Neumann and Landgraf, 2012).”
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    • cites Delville et al., 1996

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    • cites Neumann and Landgraf, 2012

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    Premisecitation

    Largely due to prior precedent (vs. pharmacological rationale), the majority of published human studies have tested OT in single doses in the 20-40 IU range, though doses as low as 10 IU and as high as 160 IU daily have been reported.

    “Largely due to prior precedent (vs. pharmacological rationale), the majority of published human studies have tested OT in single doses in the 20–40 IU range (MacDonald et al., 2011a), though doses as low at 10 IU (Goldman et al., 2011) and as high as 160 IU daily (Epperson et al., 1996a,b) have been reported.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites MacDonald et al., 2011a

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    • cites Goldman et al., 2011

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    • cites Epperson et al., 1996a

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    Interpretationreasoning

    Single-dose studies, though informative, speak somewhat peripherally to the issue of optimal dose/dosing parameters.

    “and single-dose studies, though informative, speak somewhat peripherally to this important issue.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Delineation of the role of sex and sex hormones in the response to chronic OT treatment will be critical.

    “En toto, the abovementioned sex differences indicate that delineation of the role of sex and sex hormones in the response to chronic OT treatment will be critical.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This trial demonstrated a trend-level dose-by-gender effect such that males treated with OT showed a significant clinical improvement in HAM-A scores with OT, whereas females did not.

    “This trial demonstrated a trend-level dose-by-gender effect such that males treated with OT showed a significant clinical improvement in HAM-A scores with OT, whereas females did not.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Feifel et al., 2011

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    Premisecitation

    Men and women show differences in plasma OT levels, as well as sex-specific behavioral correlations with OT.

    “men and women show differences in plasma OT levels (Ozsoy et al., 2009; Gordon et al., 2010; Holt-Lunstad et al., 2011; Weisman et al., 2012c), as well as sex-specific behavioral correlations with OT (Gordon et al., 2010; Zhong et al., 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ozsoy et al., 2009

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    • cites Gordon et al., 2010

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    • cites Holt-Lunstad et al., 2011

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    Premisecitation

    In men with fragile X syndrome, 24 IU but not 48 IU intranasal oxytocin improved eye gaze frequency, whereas 48 IU but not 24 IU decreased social-stress induced salivary cortisol levels.

    “In a study of men with fragile X syndrome, 24 IU but not 48 IU IN OT improved eye gaze frequency, whereas 48 IU but not 24 IU decreased social-stress induced salivary cortisol levels (Hall et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hall et al., 2012

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    Premisecitation

    OT has some cross-affinity with AVP receptors which mediate its potential diuretic and natriuretic effects, and these have been noted in a single case report of high-dose IN OT.

    “Aside from optimizing therapeutic effect, dosing issues are also important in terms of side effects, given that OT has some cross-affinity with AVP receptors which mediate its potential diuretic and natriuretic effects (Gimpl and Fahrenholz, 2001), and have been noted in a single case report of high-dose IN OT (Ansseau et al., 1987).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gimpl and Fahrenholz, 2001

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    • cites Ansseau et al., 1987

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    Premisecitation

    In patients with schizophrenia, 10 IU intranasal oxytocin caused a decrement in ability to identify facial emotions, whereas 20 IU improved emotion recognition in polydipsic relative to non-polydipsic patients.

    “Goldman et al. demonstrated that in patients with schizophrenia, 10 IU caused a decrement in ability to identify facial emotions (due to increased false-response rate), whereas 20 IU improved emotion recognition in polydipsic relative to non-polydipsic patients (Goldman et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Goldman et al., 2011

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  • May combine two claims.

    Premisecitation

    The three published clinical trials in schizophrenia included a disproportionate number of males (62 males treated vs. 13 females), consistent with most clinical trials of this disorder.

    “Focusing on the few multi-week clinical trials of OT in psychiatric populations, the three published clinical trials in schizophrenia included a disproportionate number of males (62 males treated vs. 13 females), consistent with most clinical trials of this disorder (Feifel et al., 2010, 2012a; Pedersen et al., 2011; Modabbernia et al., 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Feifel et al., 2010

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    • cites Pedersen et al., 2011

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    • cites Modabbernia et al., 2013

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    Premisecitation

    Across a broad range of studies, these techniques have produced congruent results, with most finding reasonable correlations between saliva and plasma oxytocin levels, and between oxytocin levels and a wide range of oxytocin-dependent biological processes.

    “these techniques have produced congruent results, with most of them finding reasonable correlations between saliva and plasma OT levels (Grewen et al., 2010; Feldman et al., 2011; Hoffman et al., 2012), and between OT levels and a wide range of OT-dependent biological processes (White-Traut et al., 2009; Grewen et al., 2010; Feldman, 2012).”
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    • cites Grewen et al., 2010

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    • cites Feldman et al., 2011

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    • cites Hoffman et al., 2012

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    Premisecitation

    Intranasal oxytocin quickly elevates peripheral oxytocin levels, and these levels remain above baseline for some time.

    “which indicate that IN OT quickly elevates peripheral OT levels, and that, these levels remain above baseline for some time.”
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    • cites Huffmeijer et al., 2012

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    • cites Weisman et al., 2012a

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    • cites Burri et al., 2008

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A recent report questioned the accuracy of radioimmunoassays and enzyme immunoassays and the necessity of sample extraction, which can change measured oxytocin levels by up to 100-fold.

    “Notably, a recent report questioned both (1) the accuracy of both radioimmunoassays (RIA) and enzyme immunoassays (EIAs) and (2) the necessity of the technical step of sample extraction which can changes by up to 100-fold the measured levels of the peptide (Szeto et al., 2011).”
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    Premisecitation

    A direct-to-the-brain path of entry after intranasal delivery of peptides and other drugs has been proposed via two possible mechanisms: intraneuronal active uptake along the olfactory or trigeminal nerve, and extraneuronal passive diffusion into the CSF through perineural clefts in the nasal epithelium.

    “Beyond this, a direct-to-the-brain path of entry after IN delivery of peptides and other drugs has been proposed via two possible mechanisms (Figure 1): (1) intraneuronal active uptake along the olfactory or trigeminal nerve into the brain; and (2) extraneuronal passive diffusion into the CSF through perineural clefts in the nasal epithelium which provide a gap in BBB (Illum, 2004; Thorne et al.,”
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    • cites Thorne et al., 2004

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    • cites Renner et al., 2012a

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    Premisecitation

    WAY-277464 exhibited an oxytocin-like anxiolytic behavioral and physiological profile and an oxytocin-like preclinical antipsychotic profile, but did not have an oxytocin-like antidepressant profile in animal tests.

    “Though it exhibited an OT-like anxiolytic behavioral and physiological profile in several animal tests (four-plate test, elevated zero maze, stress-induced hyperthermia), and also an OT-like preclinical antipsychotic profile [reversing amphetamine- and MK-801-induced disruption of prepulse inhibition (PPI)], it did not have an OT-like antidepressant profile [no reduced immobility in the tail”
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    • cites Ring et al., 2010

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    Premisecitation

    Carbetocin has about 10-fold lower affinity for the oxytocin receptor than oxytocin and lacks anxiolytic efficacy when delivered peripherally, unlike oxytocin.

    “Though a potent uterotonic agent, carbetocin has about 10-fold lower affinity for the OTR than OT (Engstrom et al., 1998; Gimpl et al., 2005), and has been shown to lack anxiolytic efficacy (elevated plus maze) when delivered peripherally, vs. OT, which has anxiolytic efficacy when delivered peripherally (McCarthy et al., 1996; Ring et al., 2006).”
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    • cites McCarthy et al., 1996

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    Premisenone given

    To date, there have been no published studies examining the time course of the brain-mediated effects of intranasal oxytocin, nor of their correlation with peripheral oxytocin levels.

    “to date, there have been no published studies examining the time course of the brain-mediated effects of IN OT, nor of their correlation with peripheral OT levels.”
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    Premisecitation

    Drugs delivered intranasally may reach the brain via active transport or diffusion from the blood compartment across the blood-CSF or blood-brain barrier.

    “In this way, IN delivery simulates IV delivery: drugs delivered IN may reach the brain via active transport or diffusion from the blood compartment across the blood-CSF or blood-brain barrier (Thorne and Frey, 2001; Morimoto et al., 2009).”
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    • cites Morimoto et al., 2009

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    Premisecitation

    Intranasal application of peptidergic drugs to the CNS has been proven since 1989 and is a delivery system increasingly utilized for a variety of drugs for a range of putative central indications.

    “IN application of peptidergic drugs to the CNS has been proven since 1989 (Frey, 1991), and is a delivery system increasingly utilized for a variety of drugs for a range of putative central indications, including memory (Benedict et al., 2007) and multiple sclerosis (Ross et al., 2004).”
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    • cites Frey, 1991

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    • cites Benedict et al., 2007

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    Premisecitation

    There are several other ways to impact the central oxytocin system, including inhibition of the non-specific enzyme that degrades oxytocin in the CSF (P-LAP) and the use of drugs that may stimulate oxytocin release from endogenous stores via serotonergic and melanocortin receptors.

    “These include inhibition of the non-specific enzyme that degrades OT in the CSF [aminopeptidase placental-leucineaminopeptidase (P-LAP) (Chai et al., 2008; Albiston et al., 2011)] and the use of drugs that may stimulate OT release from endogenous stores via the serotonergic (Jorgensen et al., 2003a) and melanocortin receptors (Sabatier, 2006) found on OT neurons.”
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    • cites Jorgensen et al., 2003a

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    Premisecitation

    A selective oxytocin receptor antagonist failed to block WAY-277464's antidepressant effects, indicating its effect may be mediated through a different receptor system.

    “was that a selective OTR antagonist failed to block these antidepressant effects, indicating WAY-27744's effect may be mediated through a different receptor system (i.e., AVPR: also infra vida section “Is Intranasal Delivery of Oxytocin the Optimal Route?”) (Ring et al., 2010)”
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    • cites Ring et al., 2010

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    Premisecitation

    Carbetocin is an uterotonic oxytocin analog with a peripheral half-life of 85-100 min, significantly longer than oxytocin's.

    “This process has produced carbetocin: an uterotonic OT analog with a peripheral half-life of 85–100 min, significantly longer than OT's (Hunter et al., 1992).”
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    • cites Hunter et al., 1992

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    Premisecitation

    Intranasal delivery capitalizes on the heavily vascularized nasal mucosa, which drains into the peripheral circulation, circumventing first pass metabolism.

    “Delivering a peptide IN capitalizes first on the heavily vascularized nasal mucosa, which drains through both fenestrated epithelium and via several facial veins (facial and sphenopalatine), into the peripheral circulation, circumventing first pass metabolism (Zhu et al., 2012).”
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    • cites Zhu et al., 2012

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    Premisecitation

    WAY-277464 is the only non-peptide oxytocin agonist with experimental evidence for an oxytocin-like behavioral profile; it had 87% of the binding affinity of oxytocin and significantly greater selectivity for the oxytocin receptor.

    “The only non-peptide OT agonist with experimental evidence for an OT-like behavioral profile is WAY-277464, which had 87% of the binding affinity of OT and significant greater selectivity for the OTR (Ring et al., 2010).”
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    • cites Ring et al., 2010

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    Premisecitation

    Neuropeptides have a brief plasma half-life, poor oral bioavailability due to degradation by plasma and gastric proteases, and limited penetrance of the blood-brain barrier due to their large size and hydrophilic nature.

    “These shortcomings include a brief plasma half-life and poor oral bioavailability due to their degradation by plasma and gastric proteases, as well as limited penetrance of the blood-brain barrier due to their large size and hydrophilic nature (McGonigle, 2012).”
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    • cites McGonigle, 2012

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    Premisecitation

    Neuropeptides have advantages over other chemical medicinal classes (evolved specificity, limited drug-drug interactions, little accumulation in tissues, few side-effects) but also carry unique liabilities as medications related to their molecular nature.

    “Though they have certain advantages over other chemical medicinal classes (i.e., evolved specificity for unique functions and receptors, limited drug–drug interactions, little accumulation in tissues, few side-effects), neuropeptides also carry unique liabilities as medications related to their molecular nature (Manning et al., 2012; McGonigle, 2012).”
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    • cites Manning et al., 2012

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    Premisecitation

    Carbetocin demonstrated an antidepressant-like profile in the forced swim test when administered peripherally and centrally, and has short-term anxiolytic effects when delivered centrally.

    “Interestingly, carbetocin did demonstrate an antidepressant-like profile in the forced swim test when administered peripherally and centrally (Chaviaras et al., 2010), and does have short-term anxiolytic effects when delivered centrally (Mak et al., 2012).”
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    • cites Chaviaras et al., 2010

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    Premisecitation

    Oxytocin is relatively selective, binding to AVP receptors with ~1% the affinity it binds to oxytocin receptors, whereas vasopressin is non-selective, binding with similar affinity to both oxytocin and AVP receptors.

    “Pertaining to OT-directed therapeutics, it is important to note that OT is relatively selective, binding to AVP receptors with ~1% the affinity it binds to OTRs, whereas AVP is non-selective, binding with similar affinity to both OTR and AVPRs (Lowbridge et al., 1977; Mouillac et al., 1995; Manning et al., 2012).”
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    • cites Lowbridge et al., 1977

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    • cites Manning et al., 2012

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  • May combine two claims.

    Interpretationcitation

    An oxytocin receptor agonist with no cross-affinity for AVPR1a would be expected to have superior anxiolytic efficacy, and a compound that acted as a dual oxytocin receptor agonist/AVPR1a antagonist might have even greater efficacy.

    “Based on this, an OTR agonist with no cross-affinity for AVPR1a would be expected to have superior anxiolytic efficacy and a compound that acted as a dual OTR agonist/AVPR1a antagonist might have even greater efficacy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AVPR1a is the most abundantly expressed in the brain, whereas AVPR1b has more limited brain expression and AVPR2 exists almost exclusively in the periphery.

    “Of these receptors, AVPR1a is the most abundantly expressed in the brain, whereas AVPR1b has more limited brain expression and AVPR2 exists almost exclusively in the periphery (Stoop, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stoop, 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent animal study revealed that AVP1a activation via desmopressin produced an anxiogenic effect, and blockade via atosiban produced an anxiolytic effect.

    “Highlighting this issue, a recent animal study revealed that AVP1a activation (via desmopressin, an AVP receptor agonist) and blockade (via atosiban, an OT/AVP1a receptor antagonist) produced anxiogenic and anxiolytic effect, respectively (Mak et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mak et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxytocin enhances neurogenesis, the beneficial effects of social support, social salience, and social memory.

    “Evidence that OT enhances neurogenesis (Leuner et al., 2012), the beneficial effects of social support (Heinrichs et al., 2003), social salience and social memory (Hurlemann et al., 2010; Guastella and MacLeod, 2012) also suggest that OT is a good candidate for such “augmentation” trials.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Leuner et al., 2012

      Not checked in the free run.

    • cites Heinrichs et al., 2003

      Not checked in the free run.

    • cites Hurlemann et al., 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A number of specific agonists and antagonists for each of the four different nonapeptide receptors have been developed and have allowed more precise delineation of the role of the different receptors in the activities of each of these nonapeptides.

    “A number of specific agonists and antagonists for each of the four different nonapeptide receptors have been developed (Manning et al., 2012), and have allowed more precise delineation of the role of the different receptors in the activities of each of these nonapeptides.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Manning et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Differences in receptor co-expression and region-specific density influence the different roles of oxytocin and vasopressin in the CNS, and many models suggest these related peptides have somewhat opposing roles in terms of anxiety and behavioral measures of coping.

    “it appears that differences in receptor co-expression and region-specific density—parameters which vary meaningfully in rodents (see Veinante and Freund-Mercier, 1995; Huber et al., 2005; Young et al., 2006; Raggenbass, 2008), and humans (Loup et al., 1991)—influence the different roles of these two nonapeptides in the CNS, and many models suggest these related peptides have somewhat opposing”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Veinante and Freund-Mercier, 1995

      Not checked in the free run.

    • cites Huber et al., 2005

      Not checked in the free run.

    • cites Young et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Increased central levels of oxytocin after intranasal administration can occur indirectly via elevated levels of oxytocin in the peripheral circulation, so the evidence does not represent definitive evidence of a direct nose-to-brain mechanism, nor whether intranasal oxytocin has advantages over peripheral or oral oxytocin in terms of brain penetration or reduced peripheral side effects.

    “On the other hand, increased central levels of OT after IN administration can occur indirectly via elevated levels of OT in the peripheral circulation, thus the evidence described above does not represent definitive evidence of a direct nose-to-brain mechanism, nor whether IN-administered OT has advantages over peripheral or even orally administered OT in terms of brain penetration or reduced”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Oxytocin (but not vasopressin) normalizes deficits in oxytocin and CD38 knockout mice, whereas both oxytocin and vasopressin normalize defects in oxytocin-receptor knockout mice, which demonstrate an autism-like profile.

    “Specifically, whereas OT (but not AVP) normalizes deficits in OT and CD38 knockout mice (Ferguson et al., 2000; Jin et al., 2007), both OT and AVP normalize defects in OT-receptor knockout mice, which demonstrate an autism-like profile (deficits in social behavior, seizures) (Sala et al., 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ferguson et al., 2000

      Not checked in the free run.

    • cites Jin et al., 2007

      Not checked in the free run.

    • cites Sala et al., 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both vasopressin and oxytocin administered intranasally have central effects.

    “Indirect support for this hypothesis comes from findings that both vasopressin and OT administered IN have central effects [Fehm et al. (2000) and references therein].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fehm et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A very recent human trial of the vasopressin V1b receptor antagonist SSR149415 showed negligible anxiolytic effects and antidepressant effects that warrant further study.

    “Also worth mention here is a very recent human trial of the vasopressin V1b receptor antagonist SSR149415, which showed negligible anxiolytic effects, and antidepressant effects that warrant further study (Griebel et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Griebel et al., 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Animal studies have the ability to efficiently deliver clinically relevant information without the expense, time, and risk-considerations inherent in human trials.

    “Animal studies have the ability to efficiently deliver clinically relevant information without the expense, time, and risk-considerations inherent in human trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Properties of an optimal pharmacological biomarker include high sensitivity and specificity for clinical outcomes; relatively inexpensive and low-risk; interpretable by clinicians in many different practice locations; a dose-response relationship; and a plausible link with pharmacology and pathogenesis.

    “Properties of an optimal pharmacological biomarker include: high sensitivity and specificity for clinical outcomes; relatively inexpensive, and low-risk; interpretable by clinicians in many different practice locations; a dose-response relationship; and a plausible link with pharmacology and pathogenesis (Dumont et al., 2005; Wiedemann, 2011; Baskaran et al., 2012; Leuchter et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dumont et al., 2005

      Not checked in the free run.

    • cites Wiedemann, 2011

      Not checked in the free run.

    • cites Baskaran et al., 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Preclinical human studies in which acute effects of drugs like oxytocin are examined on symptom proxies are much easier, less expensive, and less risky than classic randomized clinical trials.

    “Similarly, preclinical human studies in which acute effects of drugs, like OT, are examined on symptom proxies such as functional imaging changes in clinically relevant circuits or laboratory analogs of pathological conditions (e.g., CCK-induced panic) are much easier, less expensive, and less risky than classic randomized clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Biomarker-guided clinical trials may optimize the efficiency of future clinical trials, facilitating the optimal use of a shrinking pool of funding for oxytocin research.

    “Vitally, biomarker-guided clinical trials may optimize the efficiency of future clinical trials, facilitating the optimal use of a shrinking pool of funding for OT research (driven in part by OT's lack of patent exclusivity).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some single-dose studies add to the body of support for therapeutic effects, while others reveal a more complex role for oxytocin in human behavior, emotion, and cognition.

    “Some of these add to the body of support for therapeutic effects, while others do the opposite, revealing a more complex role for OT in human behavior, emotion, and cognition (De Dreu et al., 2010, 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites De Dreu et al., 2010

      Not checked in the free run.

    • cites De Dreu et al., 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Clinical trials using oxytocin can reciprocally provide useful information to evaluate the predictive validity of various animal models and proxy-symptom human paradigms.

    “As mentioned above, the third element in the bench-to-beside arc are clinical trials using OT, which can reciprocally provide useful information to evaluate the predictive validity of various animal models and proxy-symptom human paradigms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Current studies of oxytocin's augmentation effect in patients have been limited to one single-dose study and have demonstrated limited success on primary clinical endpoints.

    “Current studies of OT's “augmentation” effect in patients have been limited to one single-dose study and have demonstrated limited success on primary clinical endpoints (Guastella et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Guastella et al., 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    Some investigators suggest that it is premature to speculate about oxytocin's therapeutic potential for neuropsychiatric disorders and opine that before clinical trials, the field needs more translational studies to elucidate oxytocin's complex role.

    “These complexity-revealing findings in particular have spurred some investigators to suggest that it is premature to speculate about OT's therapeutic potential for neuropsychiatric disorders and opine that before we do clinical trials, the field needs more translational studies to elucidate OT's complex role (e.g., Grillon et al., 2012; Miller, 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Grillon et al., 2012

      Not checked in the free run.

    • cites Miller, 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Such studies will help address the vital questions delineated in this paper.

    “Such studies will help address the vital questions we have delineated in this paper.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Additional preclinical studies will not, by themselves, answer the critical therapeutic questions that face clinicians in the field.

    “For the myriad reasons discussed above, we believe that additional preclinical studies will not—by themselves—answer the critical therapeutic questions that face clinicians in the field.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The predictive validity of both forms of preclinical drug research with regard to psychiatric disorders is far from perfect.
    • Rests on an assumption: Examples abound in which efficacy or deleterious effects noted in clinical trials were not manifested in preclinical studies and vice versa.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Animal studies showing tolerance of clinically relevant preclinical effects after a certain duration of treatment may prompt longer-duration trials to evaluate this effect in humans.

    “Likewise, animal studies showing tolerance of clinically relevant preclinical effects after a certain duration of treatment may prompt longer-duration trials to evaluate this effect in humans.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Preclinical studies demonstrating dichotomous dose-dependent effects on clinically relevant measures may prompt research emphasis on wider dose ranging in phase-II studies of oxytocin.

    “For example, preclinical studies demonstrating dichotomous dose-dependent effects on clinically relevant measures may prompt research emphasis on wider dose ranging in phase-II studies of OT.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Biomarkers optimize the efficiency of clinical drug studies by facilitating the detection of early signals of drug response.

    “In drug development, biomarkers optimize the efficiency of clinical drug studies by facilitating the detection of early signals of drug response (Wiedemann, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wiedemann, 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    More single-dose studies-overwhelmingly in normal subjects-continue to be generated.

    “More single-dose studies—overwhelmingly in normal subjects—continue to be generated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Knowledge derived from both animal and human translational approaches will increase the likelihood of success of critical clinical trials.

    “Knowledge derived from both of these approaches will increase the likelihood of success of critical clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Evidence of adverse effect in animals emerging at certain doses or durations may prompt incorporation of specific safety monitoring features into oxytocin clinical trials.

    “Similarly, evidence of adverse effect in animals emerging at certain doses or durations may prompt incorporation of specific safety monitoring features into OT clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The translation of oxytocin's therapeutic promise has been remarkably slow, considering clinical studies with oxytocin are not hindered by the typical limitations imposed by non-approved investigational drugs.

    “Secondly, and somewhat in contrast, the translation of OT's therapeutic promise has been remarkably slow, considering clinical studies with OT are not hindered by the typical limitations imposed by non-approved investigational drugs (i.e., costly animal and human safety and toxicity testing before testing in proof-of-concept human trials).”
    Quote in the paperSubstantial claim
65 of 65

  • The authors state this as an assumption.

    Certain individuals (and perhaps certain diagnostic groups) have an as-yet undocumented state of more significant functional OT deficiency akin to central diabetes insipidus.

    “In addition to these known variations in the OT system, one could assume that certain individuals (and perhaps certain diagnostic groups) have an as-yet undocumented state of more significant functional OT deficiency akin to that found in central diabetes insipidus (DI).”

  • The paper relies on this without support.

    Almost all treatments for the most debilitating brain disorders are delivered chronically, with most achieving their maximal clinical effects after weeks of daily administration.

    “In stark contrast, almost all treatments for the most debilitating brain disorders are delivered chronically, with most achieving their maximal clinical effects after weeks of daily administration.”

  • The paper relies on this without support.

    Oxytocin lasts much longer in the CSF than in plasma.

    “it lasts much longer in the CSF”

  • The paper relies on this without support.

    There is very little known regarding the optimal therapeutic-dosing frequency of oxytocin.

    “there is very little known regarding its optimal therapeutic-dosing frequency (e.g., once daily, twice daily, etc.)”

  • The paper relies on this without support.

    The efficacy of alternative oxytocin delivery systems on centrally mediated processes has not yet been tested in human or animal studies.

    “Notably, the efficacy of this or other alternative OT delivery systems on centrally mediated processes has not yet been tested in human or animal studies.”

  • The paper relies on this without support.

    Carbetocin is approved in 23 countries outside the United States for post-partum hemorrhage, but there are no published studies investigating its CNS effects in humans.

    “Carbetocin—produced by Ferring Pharmaceuticals—is approved in 23 countries outside the United States for post-partum hemorrhage, but there are no published studies investigating its CNS effects in humans.”

  • The paper relies on this without support.

    The oxytocin and vasopressin systems are interleaved due to their close evolutionary relationship.

    “Due to their close evolutionary relationship, the pharmacological story of the OT system is interleaved with that of its “sister” hormone AVP.”

  • The paper relies on this without support.

    The predictive validity of both forms of preclinical drug research with regard to psychiatric disorders is far from perfect.

    “However, at present, the predictive validity of both these forms of preclinical drug research with regard to psychiatric disorders is far from perfect.”

  • The paper relies on this without support.

    Examples abound in which efficacy or deleterious effects noted in clinical trials were not manifested in preclinical studies and vice versa.

    “Examples abound in which efficacy or deleterious effects noted in clinical trials were not manifested in preclinical studies and vice versa.”

  • The paper relies on this without support.

    Rodents are not humans.

    “rodents are not humans”

  • The paper relies on this without support.

    Changes in functional imaging or laboratory tasks are not the same as changes in clinical symptoms.

    “changes in functional imaging or laboratory tasks are not the same as changes in clinical symptoms”

  • The paper relies on this without support.

    Industry has carried out phase II studies on investigational agents with far less data supporting their efficacy and safety than oxytocin.

    “As a point of comparison, phase II studies—the kind that are now needed to directly test the various hypotheses regarding OT's therapeutic utility—have been carried out by industry on investigational agents with far less data supporting their efficacy and safety.”

  • The paper relies on this without support.

    Brain-based disease imposes profound impairments.

    “the profound impairments imposed by brain-based disease”

  • The paper relies on this without support.

    Extant treatment for brain-based disease often has inadequate efficacy.

    “the often-inadequate efficacy of extant treatment”

  • The paper relies on this without support.

    There is a disheartening lack of promising, novel treatments in the pipeline.

    “a disheartening lack of promising, novel treatments in the pipeline”

  • The paper relies on this without support.

    Initial investigator-initiated clinical trials often produce negative or weak therapeutic effects.

    “These initial trials often produce negative or weak therapeutic effects.”

  • The paper relies on this without support.

    Randomized controlled trials are costly and labor-intensive.

    “randomized controlled trials are costly and labor-intensive”

  • The paper relies on this without support.

    Negative results due to type-II errors can be devastating to future studies.

    “negative results due to type-II errors (i.e., missing a significant therapeutic effect) for example, by infelicitous selection of dose(s) or dosing frequency can be devastating to future studies”
18 of 18

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The biological validity of peripheral oxytocin measurements with respect to central oxytocin patterns is debated.

    “The biological validity of peripheral oxytocin measurements with respect to central oxytocin patterns nonetheless is debated (33–35).”

    From Oxytocin reactivity during intergroup conflict in wild chimpanzees (2017) · cites this paper as [34]

  • The effects of oxytocin and what triggers oxytocin release in a given social context can both vary depending on individual differences such as sex, age, early experience, psychiatric or psychological health.

    “In addition, the effects that oxytocin has and what triggers oxytocin release in a given social context can both vary depending on individual differences such as sex, age, early experience, psychiatric or psychological health (effects of oxytocin: Bartz et al., 2011; Macdonald and Feifel, 2013; Olff et al., 2013; release of oxytocin: Sanders et al., 1990; Turner et al., 1999).”

    From Endogenous peripheral oxytocin measures can give insight into the dynamics of social relationships: a review (2014) · cites this paper as Macdonald and Feifel, 2013

  • Endogenous oxytocin may be an important regulator and a biomarker of subjects' social motivation toward, or perception of, a given social context.

    “Indeed, endogenous oxytocin may be an important regulator and a biomarker of subjects' social motivation toward, or perception of, a given social context (Bartz et al., 2011; Macdonald and Feifel, 2013).”

    From Endogenous peripheral oxytocin measures can give insight into the dynamics of social relationships: a review (2014) · cites this paper as Macdonald and Feifel, 2013

  • Both less invasive approaches (exogenous oxytocin administration and measuring endogenous peripheral oxytocin) have been criticized.

    “However, both of these less invasive approaches have been criticized (see Macdonald and Feifel, 2013 for review).”

    From Endogenous peripheral oxytocin measures can give insight into the dynamics of social relationships: a review (2014) · cites this paper as Macdonald and Feifel, 2013

  • Many studies show ameliorating effects of oxytocin on psychological stress and psychiatric disorders.

    “Many studies show ameliorating effects of oxytocin on psychological stress and psychiatric disorders (Striepens et al., 2011; Macdonald and Feifel, 2013).”

    From Endogenous peripheral oxytocin measures can give insight into the dynamics of social relationships: a review (2014) · cites this paper as Macdonald and Feifel, 2013

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Stated chronic-dose range omits a listed 20 IU dose

    Minor

    The cited chronic-dosing schizophrenia studies are described as using 24-40 IU twice daily, but Table 1 lists 20 IU twice daily during the first week of a cited Feifel trial.

  • Non-peptide agonist is given different identifiers

    Minor

    The text names the agonist WAY-277464, but the cited Ring et al. reference names the studied agonist WAY-267464.

  • Stated high daily dose conflicts with table entry

    Minor

    The text cites the Epperson studies as reporting doses as high as 160 IU daily, while Table 1 lists a 320 IU intranasal dose for one of those studies.

  • Generalized-anxiety trial dosing differs between text and table

    Minor

    The text says participants received 40 IU twice daily for three weeks, but Table 1 says they received 20 IU twice daily in the first week and 40 IU twice daily only for the next two weeks.

4 of 4

The citation lists haven’t been fetched yet

References 303 · Cited by 181

Research works printed but not linked: 1

  1. MacDonald K. MacDonald T. Wilson M. P. Feifel D. (2011b). Oxytocin improves social cognition in patients with depression. Biol. Psychiatry 69, 279S– 280S 10.1016/j.schres.2011.07.027 21840177 · DOI · Paper page

Authors
MacDonald, K., & Feifel, D.
Affiliations
University of California San Diego (US)
ORCID
Feifel, D.
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2013
Volume
7
Pages
35-35
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2013.00035
PMC
PMC3597931
OpenAlex
W2026476829
Semantic Scholar
8ae313c458c2b830604f7880bc7f8af1206f24e8
Cited by
181
References
303
Citations by year
2026: 4 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 9 · 2021: 14 · 2020: 10 · 2019: 11 · 2018: 11 · 2017: 22 · 2016: 20 · 2015: 18 · 2014: 20 · 2013: 17
FWCI
37.42
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
oxytocin, CNS drug development, brain disorders, psychopharmacology, translational research, randomized controlled trials, oxytocinergic system, anxiety disorders, depression, schizophrenia, drug discovery pipeline

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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